Dendritic cells (DCs) are the most potent professional antigen-presenting cells that play critical roles in initiation of immune responses and maintenance of immune homeostasis. Derived from bone marrow hematopoietic stem/multipotent progenitor cells, DCs reside in an immature state in peripheral nonlymphoid tissues. (Geissmann, et al., 2010 Science 327(5966): p. 656-61; Liu, et al. 2010 Immunol Rev 234(1): p. 45-54.) These immature DCs are able of efficiently taking up and processing various antigens. Upon stimulation with inflammatory cytokines or microbial components, such as lipopolysaccharide (LPS) of bacteria, immature DCs undergo a maturation process and begin to migrate to local lymph nodes, where they interact with CD40 ligand on antigen specific T cells via CD40 and mature into potent immuno-stimulatory or immuno-toleragenic cells (remove). (Geissmann, et al., 2010 Science 327(5966): p. 656-61; Randolph, et al. 2005 Nat Rev Immunol 5(8): p. 617-28; Mellman, et al. 2005 Adv Exp Med Biol 560: p. 63-7.) Maturation of DCs correlates with up-regulated expression of MHC class II and costimulatory molecules, production of immunostimulatory cytokines, and acquisition of capability to stimulate naive and antigen-specific T cells.
Intestinal mucosa is enriched with DCs, which reside in the lamina propria and regulate immune response to pathogen invasion. Maturation and function of intestinal DCs is regulated by both host factors and microbial components. Intestinal DCs detect the presence of pathogens through pattern recognition receptors, such as members of the toll-like receptor (TLR) family. Aberrant maturation and activation of intestinal DCs has been postulated to play a pathogenic role in auto-immune/inflammatory conditions, such as inflammatory bowel disease (IBD). It has been found that expression of TLR2, TLR4, CD40 is enhanced in DCs isolated from inflamed mucosa of IBD patients. Moreover, aberrant TLR signaling have been found to predispose patients to Crohn's disease. Evidence is accumulating, suggesting a potential role of targeting DCs in management of autoimmune-inflammatory conditions. However, currently, little is known about the intrinsic DC factors that can be manipulated to modulate DC maturation and functions.
Circulating monocytes derived DCs have been implicated in pathogenesis of inflammation, and the in vitro human monocytes derived dendritic cells have been widely used as a model system to explore the molecular mechanisms of DCs differentiation. Circulating monocytes derived DCs have been implicated in pathogenesis of inflammation. Previous studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL4 drive peripheral blood CD14+ monocytes differentiation to CD14−CD1a+ DCs. Several cytokines such as IL6, IL10 and γ-IFN have been shown to negatively regulate the monocytes differentiation into DCs, whereas other cytokines are reported to promote DCs differentiation. (Chomarat, et al. 2000 Nat Immunol 1(6): p. 510-4; Mitani, et al. 2000 Br J Haematol 109(2): p. 288-95; Allavena, et al. 1998 Eur J Immunol 28(1): p. 359-69; Delneste, et al. 2003 Blood 101(1): p. 143-50; Chomarat, et al. 2003 J Immunol 171(5): p. 2262-9; Iwamoto, et al. 2007 J Immunol 179(3): p. 1449-57; Gabriele, et al. 2004 Blood 103(3): p. 980-7.) Recent gene profiling analysis has revealed a vast number of differentially expressed genes during induced human CD14+ monocytes differentiation into DCs. (Le Naour, et al. 2001 J Biol Chem 276(21): p. 17920-31.) Nevertheless, the key transcriptional regulatory mechanisms underlying human monocytes to DCs differentiation remain poorly understood.